11-94492796-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005591.4(MRE11):c.6T>A(p.Ser2Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MRE11
NM_005591.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83

Publications

2 publications found

Variant links:

Genes affected

MRE11 (HGNC:7230): (MRE11 homolog, double strand break repair nuclease) This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

MRE11 Gene-Disease associations (from GenCC):

ataxia-telangiectasia-like disorder 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
prostate cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

MRE11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26788104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRE11	NM_005591.4 link	c.6T>A	p.Ser2Arg	missense_variant	Exon 2 of 20	ENST00000323929.8	NP_005582.1	P49959-1A0A024R395

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8 link	c.6T>A	p.Ser2Arg	missense_variant	Exon 2 of 20	1	NM_005591.4	ENSP00000325863.4		P49959-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251450

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5610

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111896

Other (OTH)

AF:

0.00

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ataxia-telangiectasia-like disorder

Uncertain:1

Jun 06, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This sequence change replaces serine with arginine at codon 2 of the MRE11A protein (p.Ser2Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. This variant has not been published in the literature and is not present in population databases. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.0027

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

T;.;.;T;.;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.67

T;T;T;T;T;T

M_CAP

Benign

0.078

MetaRNN

Benign

0.27

T;T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.9

L;L;.;.;.;.

PhyloP100

1.8

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.4

N;N;N;N;N;N

REVEL

Benign

0.22

Sift

Uncertain

0.0020

D;D;D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;T;D;D

Polyphen

0.68

P;P;.;.;.;.

Vest4

0.39

MutPred

0.15

Loss of glycosylation at S2 (P = 0.0234);Loss of glycosylation at S2 (P = 0.0234);Loss of glycosylation at S2 (P = 0.0234);Loss of glycosylation at S2 (P = 0.0234);Loss of glycosylation at S2 (P = 0.0234);Loss of glycosylation at S2 (P = 0.0234);

MVP

0.75

MPC

0.20

ClinPred

0.27

GERP RS

1.3

Varity_R

0.15

gMVP

0.66

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over